Robustaflavone, a naturally occurring biflavanoid, is a potent non-nucleoside inhibitor of hepatitis B virus (HBV) replication.sup.1. HBV is one of the most serious health problems in the world today, and is listed as the ninth leading cause of death by the World Health Organization.sup.2. Approximately 300 million persons are chronically infected with HBV worldwide, with over one million of those in the United States. The Centers for Disease Control estimates that over 300,000 new cases of acute HBV infection occurs in the United States each year, resulting in 4,000 deaths due to cirrhosis and 1,000 due to hepatocellular carcinoma.sup.3. The highest incidence of HBV infection occurs in the Far East and sub-Saharan Africa, where approximately 20% of the population are chronically infected.sup.4. Infection can be prevented through the use of several extremely effective recombinant vaccines.sup.5. Despite the availability of these vaccines, HBV infection remains the most significant viral pathogen infecting man, particularly in under-developed countries.
Preliminary in vitro evaluations had shown that robustaflavone possesses anti-hepatitis B activity comparable to several nucleoside analogues currently in clinical trialsl, as well as acts synergistically with these agents.sup.22. Robustaflavone was first.sup.6 isolated in 1973, as its hexa-O-methyl ether, from leaf extracts of Agathis robusta, and later.sup.7 in larger quantities from the seed-kernels of Rhus succedanea. While robustaflavone represents an important lead compound in the search for potential anti-hepatitis B agents, no total synthesis of robustaflavone has been reported to date. A recent synthesis of a related biflavanoid, amentoflavone (I8,II3'-biapigenin), which consists of two apigenin units connected via a biaryl linkage between respective 8- and 3'-positions, was achieved using Suzuki coupling.sup.8 of an apigenin 8-boronic acid derivative with an appropriate 3'-iodoapigenin analogue.sup.9. However, there is no disclosure or suggestion that this approach can be extended to the total synthesis of robustaflavone.